Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism.

Venous thromboembolism is a serious, potentially lethal health problem affecting 1 per 1,000 people annually (1-3). Major surgery, fractures, complicated pregnancy, the use of oral con- traceptives, and immobilization increase the risk of thrombosis. In addition, thrombosis is often familial, suggesting that genetic risk factors are involved Until recently, the major genetic defects known to predispose for thrombosis were deficiencies of antithrombin III, protein C, and protein S. Together these did not account for more than 5-10% of the cases (3-5, 7). In the last year, hereditary activated protein C (APC)' resistance, has been identified as a basis for a majority of cases of familial thrombosis (8-13). In contrast to other genetic de- fects associated with thrombosis, APC resistance is highly prev- alent in the general population (8, 10). It afflicts affected individuals with a life-long increased risk of thrombosis. APC resistance, its molecular basis, and a short description of the protein C anticoagulant system will be presented.